17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) is a selective progesterone receptor modulator, it is being tested for treatment of progesterone sensitive myomata.
International patent application WO 97/41145 disclosed for the first time the preparation of 17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione). In example 9 it is characterized as light-yellow powder with a melting point of 116° C. (purity: 98.06%, characteristic FT-IR absorption bands at: 1124, 1235, 1370, 1446, 1518, 1612, 1663, 1734, 2940 cm−1).
According to the published international patent applications of WO 01/47945 and WO 01/74840 the obtained 17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) was light-yellow powder as well having a melting point of 116° C. (purity: 98.87%, 98.06%, characteristic FT-IR absorption bands at: 1124, 1235, 1370, 1446, 1518, 1612, 1662, 1734, 2940 cm−1)
Final products of the above mentioned procedures were obtained by expensive purification processes. First, the crude product was purified by chromatography, then after evaporation, the obtained foam was treated in ultrasonic cleaner.
International patent application WO 2009001148 discloses another preparation process wherein the final product is obtained by chromatographic purification and evaporation (impurity: 0.5%, melting point: 118° C., solid-state characteristics determined by analytical technology are shown in FIG. 1-4).
Using preparation processes known in the literature, we have found that the products could not crystallize spontaneously. The purification of the crude product is expensive, difficult and not efficient enough. As the product can not be crystallized, wich is the most efficient purification procedure, more difficult and expensive cleaning processes must be applied (for example chromatographic purification). The amorphous product has small grain size, so the filtration thereof is quite difficult. On the one part the unsuitable chemical stability of the amorphous form makes the drying and the storage of the product uneasy, and on the other part, the grain size and electrostatical properties of this form makes the blending, packing, sampling etc. difficult.
It must be emphasized that the pharmaceutical utility of a compound depends on the purity of the final product. To develop a reproducible large-scale preparation, it is very important to obtain a product wich can be filtered and dried easily. From this point of view, it is also important for the product to remain stable for a long time without using any special storage conditions.
From a pharmaceutical point of view, the use of the amorphous product obtained by the above-mentioned procedures is not economical and very difficult. Thus, it is necessary to develop a process to obtain a pure crystalline product because, on the one hand, it ensures suitable pharmaceutical properties and on the other hand, it reduces the cost of the purification process significantly.
In view of the pharmaceutical value of a compound, it is of prime importance to obtain it with excellent purity. It is also important to be able to synthetize it by means of a process that can readily be converted to industrial scale, especially in a form that allows rapid filtration and drying. From the above technological and product quality point of view certain polymorphs, via a specific synthetic route, provide unique opportunity to fulfill these requirements. Therefore, there is a pharmaceutical need to find proper polymorphs and crystallization processes that advantageously provide a compound in excellent purity with rapid filtration and drying properties on an industrial scale.
The chemical purity of the product should be improved to obtain the active ingredient in a sufficiently high quality as required for development of a product for human use. Therefore there is a need to find new polymorphic forms in chemically and physically pure form and an industrial process leading to new solid forms that can be advantageous for different pharmaceutical reasons as explained above. To solve this need we have carried out a thorough research to find new polymorphic forms of 17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione). Those of ordinary skilled in the art would know that an a priori knowledge of what kind of polymorphs of a given compound might exsist and what process leads to their formation does not exsist. This should be discovered by a purely empirical process which is the subject of the present invention.
It has now been discovered that stable crystalline form of 17α-acetoxy-21-methoxy-11β-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) can be prepared.